1. Field of the Invention
This disclosure relates to the fields of medicine, pathology, molecular biology and onocology. In particular, peptides have been identified that inhibit PELP1 interactions with molecules that lead to oncogenic signaling. The use of such peptides in treating cancers is also disclosed.
2. Related Art
Endocrine therapy for breast cancer patients targets the estrogen receptor alpha (ERα) with either antiestrogens or aromatase inhibitors (Osborne, 1998; Harvey et al., 1999). Although hormonal therapy targeting ERα is effective for the treatment of breast cancer, a significant number of patients develop resistance leading to metastatic disease. These tumors still have ERα signaling including several oncogenic ERα coregulators that are upregulated and promote breast cancer therapy resistance and metastasis; therefore, targeting these coregulators could be a promising cancer therapeutic (Bekri et al., 1997; Habashy et al., 2010). Current therapeutic approaches are ineffective in targeting oncogenic coregulators that are involved in therapy resistance. Cancer stem cells (CSCs) may also play a role in therapy resistance, and therefore therapies must completely eradicate the CSCs to be effective.
One coactivator of ERα that is known to be upregulated in breast cancer, promote therapy resistance and metastasis, and provide cancer cells with a distinct growth and survival advantage is proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) (Rajhans et al., 2007; Girard et al., 2013; Vadlamudi et al., 2001; 2007; Nair et al., 2010a). PELP1 overexpression results in cellular transformation, anchorage-independence and tumor growth in xenograft studies and is linked to shorter breast cancer specific survival (Habashy et al., 2010; Rajhans et al., 2007). In invasive breast cancers, PELP1 localizes to the cytoplasm and correlates with increased resistance to tamoxifen treatment (Kumar et al., 2009). PELP1 has several protein-protein interactions that play a central role in breast cancer progression (Nair et al., 2011; Vallabhaneni et al., 2011; Cortez et al., 2012). Inhibition of PELP1 with siRNA liposomes reduces tumor growth in a breast cancer xenograft model, suggesting that PELP1 is a promising potential therapeutic target (Cortez et al., 2012).
Estrogen signaling contributes to epigenetic changes through the induction of histone modifications at ERα target gene promoters which play a role in the regulation of transcription (Mann et al., 2011). The methylation of histone tails can have distinct effects on transcription depending on the chromosomal location, the combination of posttranslational modifications, and the enzyme involved in the particular modification (Nishioka et al., 2002). PELP1 couples ERα with epigenetic modifiers at target genes and recognizes histone demethylation (Mann et al., 2013). The epigenetic modifier G9a is a SET domain-containing lysine methyltransferase that transfers methyl groups to the lysine residues 9 and 27 of histones with a 10-20 fold higher activity than Suv39h1 (Tachibana et al., 2001). G9a is mainly responsible for monomethylation and dimethylation of H3K9 and contains ankyrin repeats, which may be involved in intracellular protein-protein interactions (Milner et al., 1993; Brown et al., 2001). These ankyrin repeat domains bind with strong preference to N-terminal H3 peptides containing mono- or dimethyl K9, making it a methyltransferase that generates and reads the same epigenetic mark (Collins et al., 2008). G9a functions as a coregulator of ERα and overexpression induces an invasive cancer phenotype (Purcell et al., 2011; Kondo et al., 2008; Chen et al., 2010). Inhibition of G9a with small molecules has the potential to be an effective therapeutic for cancer (Kubicek et al., 2007; Liu et al., 2009). Although these studies implicate PELP1 and G9a signaling as playing a role in breast cancer, it is unknown whether these pathways coordinately influence breast cancer progression and therapy resistance, or whether targeting this interaction would provide any beneficial effect.